Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy

Inclusion Criteria

- INCLUSION CRITERIA - RECIPIENT:

- Diagnosed with severe aplastic anemia characterized by all of the following:

1. Bone marrow cellularity less than 30 percent (excluding lymphocytes)

2. Transfusion dependence for platelets and/or RBCs

3. Neutropenia (absolute neutrophil count less than 500 cells/microL) OR for
patients receiving granulocyte transfusions, absolute neutrophil count < 500
cells/microL before beginning granulocyte transfusions].)

OR

- Diagnosed with myelodysplastic syndrome characterized by Refractory Cytopenia with
Unilineage Dysplasia (RCUD) or (Refractory anemia with ringed sideroblasts (RARS), or
Refractory cytopenia with multi-lineage dysplasia (RCMD) or refractory anemia with
excess blasts (RAEB) type I or type II, MDS-imc;assofoed (MDS-U) and at least one of
the following:

1. Neutropenia [(absolute neutrophil count < 500 cells/microL) OR for patients
receiving granulocyte transfusions, absolute neutrophil count < 500
cells/microL before beginning granulocyte transfusions]) and history of 1 or
more opportunistic infections related to neutropenia. OR

2. History of severe aplastic anemia transformed to MDS

- Intolerance of or failure to respond standard immunosuppressive therapy.

- Availability of at least one HLA-haploidentical (i.e. greater than or equal to 5/10
and less than or equal to 8/10 HLA match) related donor (HLA-A, B, C, DR, and DO
loci) who is available to donate CD34+ cells (6-75 years old).

- Availability of at least one 4/6 HLA-matched (HLA-A, B, and DR loci) cord blood unit
from the National Marrow Donor Program (NMDP). The cord blood unit must contain a
minimum TNC (prior to thawing) of at least 1.5 x 10(7) cells per kilogram of
recipient body weight with the following exception: if the minimum criterion of TNC
is not met the cord unit must contain at least 1.7 x 10(5) CD34 plus cells/kg (prior
to thawing).

- Ages 4-55 years inclusive.

- Ability to comprehend the investigational nature of the study and provide informed
consent. The procedure will be explained to subjects aged 4-17 years with formal
consent being obtained from parents or legal guardian.

EXCLUSION CRITERIA - RECIPIENT:

- Availability of an HLA identical or 9/10 HLA matched(HLA A, B, C, DR, and DO
loci-relative to serve as a stem cell donor.

- The patient is deemed to be a candidate for a 6/6 HLA matched unrelated stem cell
transplant (availability of a donor and resources required for such a transplant).

- ECOG performance status of 2 or more.

- Major anticipated illness or organ failure incompatible with survival from transplant

- Severe psychiatric illness. Mental deficiency sufficiently severe as to make
compliance with the transplant treatment unlikely and making informed consent
impossible.

- Positive pregnancy test for women of childbearing age.

- HIV positive

- Diagnosis of Fanconi's anemia or dyskeratosis congenita.

- Diffusion capacity of carbon monoxide (DLCO) less than 40 percent predicted (patients
under the age of 10 may be excluded from this criterion if they have difficulty
performing the test correctly and thus are unable to have their DLCO assessed).

- Left ventricular ejection fraction less than 40 percent (evaluated by ECHO) or less
than 30 percent (evaluated by MUGA)

- Transaminases greater than 5x upper limit of normal (when transaminases are elevated,
the subject may be excluded at the discretion of the PI).

- Serum bilirubin greater than 4 mg/dl

- Creatinine clearance less than 50 cc/min by 24 hr urine collection (adjusted for body
surface area, i.e.50 ml/min/1.73m(2))

- Failure to collect an adequate number of CD34+ cells (i.e. greater than or equal 2 x
10(6) CD34+ cells/kg) for transplantation from the subject's haploidentical relative.

- Presence of an active infection not adequately responding to appropriate therapy

- History of a malignant disease liable to relapse or progress within 5 years

INCLUSION CRITERIA - RELATED HAPLOIDENTICAL DONOR DONATING PURIFIED CD34 PLUS CELLS:

- HLA mismatched family donor (greater than or equal to 5/10 and less than or eqhal to
8/10 HLA matched (HLA-A, B, C, DR and DO loci) who is available to donate CD34+
cells.

- Ages 6-75 inclusive

- Weight greater than or equal to 18 kg.

- For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian
who is not the recipient of the transplant and informed assent: The process will be
explained to the minor on a level of complexity appropriate for their age and ability
to comprehend.

EXCLUSION CRITERIA - RELATED DONOR (ANY OF THE FOLLOWING):

- Pregnant or lactating.

- A pediatric haploidentical donor will be excluded if a suitable adult haploidentical
donor is available.

- Unfit to receive filgrastim (G-CSF) and undergo apheresis (history of stroke, MI,
unstable angina, uncontrolled hypertension, severe heart disease or palpable spleen).

- HIV positive (Donors who are positive for HBV, HCV or HTLV I/II, T. cruzi [Chagas]
may be used at the discretion of the investigator following counseling and approval
from the recipient).

- Sickling hemoglobinopathies including HbSS, HbAS, HbSC

- Severe psychiatric illness. Mental deficiency sufficiently severe as to make
compliance with the BMT treatment unlikely and making informed consent impossible.